932 Identification of pharmacologic inhibitors of specific kinases that prevent IL-4-induced macrophage polarization

PURPOSE: Macrophages polarize towards different polarization states with distinct and partly opposing functions in many skin diseases. Macrophages polarized by IL-4 have important roles during wound healing, fibrosis, parasitic inflammation, chronic allergic contact dermatitis or squamous cell skin cancer. In contrast, macrophages polarized by IFNγ-induced have important antitumorigenic roles or function in the killing of intracellular pathogens. This suggests that selectively inhibiting IL-4-induced macrophage polarization without impairing IFNγ-induced polarization would have therapeutic benefit in many common skin diseases. METHODS: We performed global quantitative proteomic and phospho-proteomic analyses of polarizing macrophages, as well as chemical screens with kinase inhibitors of specific cellular signaling pathways in order to identify pharmacologic inhibitors that block selectively IFNγ-induced macrophage polarization and to define the signaling mechanisms that are driving this polarization process. RESULTS: We discovered pharmacologic inhibitors for specific kinases that potently block IL-4-induced macrophage polarization without affecting IFNγ-induced polarization, both in human and mouse macrophages. We could also show that inhibition specifically of IL-4-induced macrophage polarization can reduce pathologic neovascularization. CONCLUSIONS: Based on our findings we propose a signaling axis that is critical for IL-4-induced macrophage polarization and that can be inhibited through small chemicals without affecting normal macrophage functions. The molecular characterization of IL-4-induced macrophage polarization mechanisms and the validation of the findings with multiple class-specific kinase inhibitors in both human and mouse macrophages provides the basis for future clinical trials of these kinase inhibitors for dermatologic skin conditions that are promoted by IL-4-induced activated macrophages.